The present invention relates to staurosporin derivatives or pharmaceutically acceptable salts thereof, which are useful for the treatment of tumors. Further, the present invention relates to enhancers for activity of an antitumor agent.
As staurosporin derivatives effective for the treatment of tumors, UCN-1 in WO89/7105, CGP41251 in EP657164A, etc. are described. 
The staurosporin derivatives as described in the above two literatures, Japanese Published unexamined Application No.62-220196, WO94/20106, WO95/32974, WO95/32975, WO95/32976, EP624590A, etc. are characterized in that in the general formula (I) described below, both of R2 and R3 are hydrogen.
As the staurosporin derivatives wherein in the general formula (I) described below, at least one of R2 and R3 is not hydrogen, compounds described in Japanese Published Unexamined Application No.3-72485, Japanese. Published. Unexamined Application No.3-220194 and Japanese Published Unexamined Application No. 4-364186, compounds described in WO94/6799, and compounds described in WO97/5141 are known. However, Japanese Published Unexamined Application No.3-72485, Japanese Published Unexamined Application No.3-220194 and Japanese Published Unexamined Application No.4-364186 disclose only compounds wherein in the general formula (I) described below, R1 is hydrogen, and R2 and R3 are hydrogen, nitro, amino, formyl, carboxy, lower alkoxycarbonyl, hydroxymethyl or hydroxy, and these compounds are used for inhibition of platelet aggregation, and their effect on the treatment of malignant tumors is not shown. WO94/6799 disclose only compounds wherein in the general formula (I) described below, R1 is hydrogen, and R2 and R3 are hydrogen, halogen, formyl, lower alkanoyl or lower alkoxy, and these compounds are used for the treatment of thrombocytopenia, and their effect on the treatment of malignant tumors is not shown. Further, the compounds described in WO97/5141 are characterized in that in the general formula (I) described below, compounds are the derivatives which have a ketone or an oxime at the 11-position, and there are neither specific compounds nor synthetic intermediates thereof wherein in the general formula (I) described below, at least one of R2 and R3 is not hydrogen.
On the other hand, it is known that some of these compounds in the prior art have strong affinity for human xcex11 acidic glycoprotein (hereinafter referred to as hxcex11AGP), which is contained in human plasma [Pharmacogenetics, 6, 411 (1996)]. The pharmacokinetics etc. of such compounds can be influenced by the strong affinity for hxcex11AGP and the expected efficacy of the compounds upon administration into humans can also be influenced. Thus, staurosporin derivatives with low affinity for hxcex11AGP are desired. The above-described staurosporin derivatives wherein in the general formula (I) described below, both of R2 and R3 are hydrogen are shown to have strong bonding to hxcex11AGP [Abstracts of 118th The Pharmaceutical Society of Japan Annual Meeting, 4, 43 (1998)].
On the other hand, it is known that UCN-01 shows a synergistic effect when combined with known anticancer agents having actions on DNA or antimetabolites, such as Cisplatin, Mitomycin C or 5-Fluorouracil, in vitro and in vivo [Proc. Am. Assoc. Cancer Res., 33, 514 (Publication No. 3072) (1992) and Cancer Chemotherapy Pharmacology, 32, 183 (1993)]. The mechanism of bringing about the is estimated as follows: when DNA in cancer cells is damaged by anticancer agents having actions on DNA or by antimetabolites, the cancer cells act for repairing the DNA damage by stopping their cell cycle at the G2 or S stage (accumulation action at the G2 or S stage), and UCN-01 abrogates this accumulation action, thus promoting progress of the cell cycle, thereby depriving the cancer cells of a chance to repair the DNA damage and leading the cancer cells to apoptosis [Clinical Cancer Res., 2, 791 (1996), Cell Growth and Differentiation, 8, 779 (1997), J. Natl. Cancer Inst., 88, 956 (1996), Proc. Am. Assoc. Cancer Res., 39, 70 (Publication No. 476) (1998)]. This action is called abrogation action on accumulation action at the G2 or S stage, and caffeine is known as a known chemical having this abrogation action, but its concentration for inducing action is as very high as mmol/L level, and so there is little clinical usefulness. [Cancer Res., 55, 1643 (1995)].
Among such compounds, UCN-01, which can abrogate accumulation action at the G2 or S stage at a low concentration of 100 mmol/L or less, is considered to be the strongest abrogation inducer known so far.
On the other hand, UCN-01 binds strongly to hxcex11AGP to lose its biological activity, thus making administration of a large amount of UCN-01 clinically necessary and simultaneously necessitating attention to the interaction among chemicals on hxcex11AGP, and therefore it is anticipated that the possibility of using UCN-01 as an abrogation inducer on accumulation action at the G2 and S stage is limited [Cancer Res., 58, 3248 (1998)].
Accordingly, there is demand for enhancers for activity of antitumor agents, which are capable of exerting abrogation action on accumulation action at the G2 and S stage while preventing binding to a series of hxcex11AGPs.
An object of the present invention is to provide staurosporin derivatives or pharmaceutically acceptable salts thereof, which are useful for the treatment of tumors. Another object is to provide enhancers for activity of antitumor agents.
The present invention relates to antitumor agents comprising a staurosporin derivative or a pharmaceutically acceptable salt thereof, as an active ingredient, which is represented by the general formula (I): 
wherein
R1 represents hydrogen, hydroxy, or lower alkoxy;
R2 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkadienyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, halogen, nitro, formyl, COR6  less than wherein R6 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, NR7R8 {wherein R7 and R8 are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group, or are combined with their adjacent N to form a substituted or unsubstituted heterocyclic group (the heterocyclic group formed by R7 and R8 together with their adjacent N may contain an oxygen atom, a sulfur atom, or another nitrogen atom)}, OR9 (wherein R9 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, or substituted or unsubstituted aryl), or SR10 (wherein R10 represents substituted or unsubstituted lower alkyl, or substituted or unsubstituted aryl) greater than , NR11R12  less than wherein R11 and R12 are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, COR13 {wherein R13 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, lower alkoxycarbonyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, OR9A (wherein R9A has the same meaning as defined for R9 above) NR7AR8A (wherein R7A and R8A have the same meaning as defined for R7 and R8 above, respectively)}, CSR13A (wherein R13A has the same meaning as defined for R13 above), SO2R13B (wherein R13B has the same meaning as defined for R13 above), or a residue of an amino acid, excluding a hydroxyl group in a carboxylic group of the amino acid (a functional group in the amino acid may be protected with a protective group) greater than , or OR14 {wherein R14 represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, cycloalkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aroyl, or CONR7BR8B (wherein R7B and R8B have the same meanings as defined for R7 and R8 above, respectively)};
R4 represents hydrogen or substituted or unsubstituted lower alkyl;
R5 represents NR11AR12A (wherein R11A and R12A have the same meanings as defined for R11 and R12 above, respectively); and
R3 has the same meaning as defined for R2, with the proviso that R2 and R3 are not simultaneously hydrogen.
Further, the present invention relates to staurosporin derivatives or pharmaceutically acceptable salts thereof, which are represented by the general formula (IA): 
wherein
R2A represents hydrogen, hydroxy, halogen, formyl, nitro, amino, COR6A1 (wherein R6A1 represents substituted or unsubstituted lower alkyl, hydroxy, or substituted or unsubstituted lower alkoxy), OR14A1 (wherein R14A1 represents substituted or unsubstituted lower alkyl), lower alkyl, substituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkadienyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, COR6A3 (wherein R6A3 has the same meaning as defined for R6A2 below), NR11A2R12A2 (wherein R11A2 and R12A2 have the same meanings as defined for R11A1 and R12A1 below, respectively), or OR14A3 (wherein R14A3 has the same meaning as defined for R14A2 below);
when R2A represents hydrogen, hydroxymethyl, hydroxy, halogen, formyl, nitro, amino, COR6A1 (wherein R6A1 represents substituted or unsubstituted lower alkyl, hydroxy, or substituted or unsubstituted lower alkoxy), or OR14A1 (wherein R14A1 represents substituted or unsubstituted lower alkyl),
R3A represents lower alkyl, substituted lower alkyl (the substituted lower alkyl is not hydroxymethyl), substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkadienyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, COR6A2  less than wherein R6A2 represents substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, NR7A1R8A1 (wherein R7A1 and R8A1 have the same meanings as defined for R7 and R8 above, respectively), OR9A1 (wherein R9A1 represents substituted or unsubstituted lower alkenyl, cycloalkyl, or substituted or unsubstituted aryl), or SR10A1 (wherein R10A1 has the same meaning as defined for R10 above) greater than , NR11A1R12A1 (wherein NR11A1 and R12A1 have the same meanings as defined for R11 and R12 above, respectively, with the proviso that R11A1 and R12A1 are not simultaneously hydrogen), or OR14A2 {wherein R14A2 represents substituted or unsubstituted lower alkenyl, cycloalkyl, substituted or unsubstituted lower alkanoyl, substituted or unsubstituted aroyl, or CONR7B1R8B1 (wherein R7B1 and R8B1 have the same meanings as defined for R7 and R8 above, respectively)};
when R2A represents lower alkyl, substituted lower alkyl (the substituted lower alkyl is not hydroxymethyl), substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkadienyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, COR6A3 (wherein R6A3 has the same meaning as defined for R6A2 above), NR11A2R12A2 (wherein R11A2 and R12A2 have the same meanings as defined for R11A1 and R12A1 above, respectively), or OR14A3 (wherein R14A3 has the same meaning as defined for R14A2 above),
R3A represents substituted or unsubstituted lower alkyl substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkadienyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, halogen, nitro, formyl, COR6A4 [wherein R6A4 represents substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, NR7A2R8A2 {wherein R7A2 and R8A2 have the same meanings as defined for R7 and R8 above, respectively}, OR9A2 (wherein R9A2 has the same meaning as defined for R9 above), or SR10A2 (wherein R10A2 has the same meaning as defined for R10 above)], NR11A3R12A3 (wherein R11A3 and R12A3 have the same meanings as defined for R11 and R12 above, respectively), or OR14A4 (wherein R14A4 has the same meaning as defined for R14 above);
R1A has the same meaning as defined for R1 above; and
R4 and R5 have the same meanings as defined above, respectively.
In particular, the staurosporin derivatives or the pharmaceutically acceptable salts thereof, wherein R1A is hydroxy, are preferable.
Further, the present invention relates to staurosporin derivatives or pharmaceutically acceptable salts thereof, which are represented by the general formula (IB): 
wherein R1B, R2B and R3B represent groups defined for the above R1, R2 and R3, respectively, except when R1 is hydrogen and R2 and R3 are the same or different and represent hydrogen, nitro, amino, carboxy, lower alkoxycarbonyl, hydroxy or hydroxymethyl, and when R1 is hydrogen and R2 and R3 are the same or different and represent hydrogen, halogen, formyl, lower alkanoyl or lower alkoxy; and R4 and R5 have the same meanings as defined above, respectively.
In particular, the staurosporin derivatives or the pharmaceutically acceptable salts thereof, wherein R1B is hydroxy, are preferable.
Further, the present invention relates to staurosporin derivatives or pharmaceutically acceptable salts thereof, wherein in the general formula (IA),
R2A represents amino, halogen, formyl or hydroxy, and
R3A represents substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, lower alkyl, substituted lower alkyl (the substituted lower alkyl is not hydroxymethyl), or NHCOR13A1 (wherein R12A1 has the same meaning as defined for R13 above); or
R2A represents substituted or unsubstituted lower alkenyl, a substituted or unsubstituted lower alkynyl, lower alkyl, substituted lower alkyl (the substituted lower alkyl is not hydroxymethyl), or NHCOR13A2 (wherein R13A2 has the same meaning as defined for R13 above), and
R3A represents substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, amino, substituted or unsubstituted lower alkyl, or NHCOR13A (wherein R13A has the same meaning as defined for R13 above).
In particular, the staurosporin derivatives or the pharmaceutically acceptable salts thereof, wherein R1A is hydroxy, are preferable.
Further, the present invention relates to the staurosporin derivatives or the pharmaceutically acceptable salts thereof, wherein in the general formula (IB), R2B and R3B are the same or different and represent substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, amino, halogen, formyl, hydroxy, substituted or unsubstituted lower alkyl, or NHCOR13 (wherein R13 has the same meaning as defined above).
In particular, the staurosporin derivatives or the pharmaceutically acceptable salts thereof, Wherein R1B is hydroxy, are preferable.
Further, the present invention relates to a pharmaceutical composition comprising at least one staurosporin derivative or pharmaceutically acceptable salt thereof, represented by the general formula (IA) or (IB), and a pharmaceutically acceptable carrier.
Further, the present invention relates to enhancers for activity of an antitumor agent, comprising the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof, as an active ingredient. Further, the present invention relates to the enhancers for activity enhancing the activity of an antitumor agent by abrogating accumulation action at the G2 or S stage of the cell cycle.
Further, the present invention relates to agents for abrogating accumulation action at the G2 or S stage of the cell cycle, comprising the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof, as an active ingredient.
Further, the present invention relates to enhancers for activity of an antitumor agent, comprising the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt, as an active ingredient. Further, the present invention relates to the enhancers for activity enhancing the activity of an antitumor agent by abrogating accumulation action at the G2 or S stage of the cell cycle.
Further, the present invention relates to agents for abrogating accumulation action at the G2 or S stage of the cell cycle, comprising the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt, as an active ingredient.
Further, the present invention relates to antitumor agents comprising at least one staurosporin derivative or pharmaceutically acceptable salt thereof, represented by the general formula (IA) or (IB).
Further, the present invention relates to a pharmaceutical composition comprising at least one staurosporin derivative or pharmaceutically acceptable salt thereof, represented by the general formula (IA) or (IB).
Further, the present invention relates to a method for treating a malignant tumor, comprising the step of administering a therapeutically effective amount of the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof.
Further, the present invention relates to a method for enhancing the activity of an antitumor agent, comprising the step of administering a therapeutically effective amount of the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof.
Further, the present invention relates to a method for abrogating accumulation action at the G2 or S stage of the cell cycle, comprising the step of administering a therapeutically effective amount of the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof.
Further, the present invention relates to use of the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent.
Further, the present invention relates to use of the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof for the manufacture of an enhancer for activity of an antitumor agent.
Further, the present invention relates to use of the staurosporin derivative represented by the general formula (I) or the pharmaceutically acceptable salt thereof for the manufacture of an agent for abrogating accumulation action at the G2 or S stage of the cell cycle.
Further, the present invention relates to a method for treating a malignant tumor, comprising the step of administering a therapeutically effective amount of the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt thereof.
Further, the present invention relates to a method for enhancing the activity of an antitumor agent, comprising the step of administering a therapeutically effective amount of the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt thereof.
Further, the present invention relates to a method for abrogating accumulation action at the G2 or S stage of the cell cycle, comprising the step of administering a therapeutically effective amount of the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt thereof.
Further, the present invention relates to use of the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt thereof for the manufacture of an antitumor agent.
Further, the present invention relates to use of the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt thereof for the manufacture of an enhancer for activity of an antitumor agent.
Further, the present invention relates to use of the staurosporin derivative represented by the general formula (IA) or (IB) or the pharmaceutically acceptable salt thereof for the manufacture of an agent for abrogating accumulation action at the G2 or S stage of the cell cycle.
Hereinafter, the compound represented by the general formula (I) is referred to as Compound (I). The compounds of other formula numbers are referred to in the same manner.
In the definition of each group in Compound (I), Compound (IA) and Compound (IB), the lower alkyl means the straight-chain or branched alkyl having 1 to 8 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl, octyl, etc.
The lower alkyl moieties of the lower alkoxy and lower alkoxycarbonyl have the same meaning as defined for the lower alkyl described above.
The cycloalkyl means the cycloalkyl having 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.
The lower alkenyl means the straight-chain or branched alkenyl having 2 to 6 carbon atoms, for example, vinyl, allyl, butenyl, pentenyl, hexenyl, etc.
The lower alkadienyl means the straight-chain or branched alkadienyl having 5 to 8 carbon atoms, for example, pentadienyl, hexadienyl, heptadienyl, octadienyl, etc.
The lower alkynyl means the straight-chain or branched alkynyl having 2 to 8 carbon atoms, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, etc.
The lower alkanoyl means the straight-chain or branched alkanoyl having 2 to 9 carbon atoms, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, etc.
The aryl and the aryl moiety of the aroyl mean, for example, phenyl, naphthyl, etc.
The heterocyclic group means, for example, aliphatic heterocyclic groups such as pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperidino, morpholino and piperadinyl, or aromatic heterocyclic groups such as furyl, thienyl, pyrrolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl and quinazolinyl.
The heterocyclic group formed together with their adjacent N (the heterocyclic group formed together with their adjacent N may contain oxygen, sulfur, or other nitrogen atoms) means pyrrolidinyl, morpholino, thiomorpholino, N-methylpiperadinyl, pyrazolidinyl, piperidino, piperadinyl, homopiperadinyl, indolyl, isoindolyl, etc.
The halogen means an atom of fluorine, chlorine, bromine or iodine atom.
The amino acid means xcex1-amino acids such as glycine, alanine, proline, glutamic acid, lysine, serine, cysteine, cystine, threonine, valine, methionine, leucine, isoleucine, norleucine, phenylalanine, tyrosine, thyroxine, hydroxyproline, tryptophan, aspartic acid, arginine, ornithine and histidine. The protective group for a functional group in the amino acid is the one used usually in peptide synthesis, and means, for example, benzyloxycarbonyl, tert-butoxycarbonyl, benzyloxy, tert-butoxy, methoxybenzenesulfonyl, etc.
The substituents in the substituted lower alkyl and substituted lower alkoxy include 1 to 3 substituents which are the same or different, for example, halogen, carboxy, lower alkoxycarbonyl, lower alkanoyl, aryl, substituted aryl (the substituents in the substituted aryl have the same meanings as defined for the substituents in the substituted aryl described below), a heterocyclic group, a substituted heterocyclic group (the substituents in the substituted heterocyclic group have the same meanings as defined for the substituents in the substituted heterocyclic group described below), CONR15R16 {wherein R15 and R16 are the same or different and represent hydrogen, hydroxy, aralkyl, lower alkyl, lower alkenyl, aryl, substituted aryl (the substituents in the substituted aryl have the same meanings as defined for the substituents in the substituted aryl described below), a heterocyclic group, or a substituted heterocyclic group (the substituents in the substituted heterocyclic group have the same meanings as the substituents in the substituted heterocyclic group described below), or are combined with their adjacent N to form a heterocyclic group (the heterocyclic group formed together with their adjacent N may contain oxygen, sulfur, or other nitrogen atoms)}, NR17R18 (wherein R17 and R18 are the same or different and represent hydrogen, lower alkyl, lower alkenyl, lower alkanoyl, aroyl, aryl, substituted aryl (the substituents in the substituted aryl have the same meanings as defined for the substituents in the substituted aryl described below), a heterocyclic group, a substituted heterocyclic group (the substituents in the substituted heterocyclic group have the same meanings as the substituents in the substituted heterocyclic group described below), substituted lower alkyl {the substituted lower alkyl is replaced by at least one of hydroxy, lower alkoxy, O(CH2CH2O)nR19 (wherein n is an integer of 1 to 15, and R19 is lower alkyl), oxo, carboxy, lower alkoxycarbonyl, aryl, substituted aryl (the substituents in the substituted aryl have the same meanings as defined for the substituents in the substituted aryl described below), a heterocyclic group, a substituted heterocyclic group (the substituents in the substituted heterocyclic group have the same meanings as defined for the substituents in the substituted heterocyclic group described below), CONR15AR16A (wherein R15A and R16A have the same meanings as defined for R15 and R16 described above, respectively), amino, lower alkylamino, and di(lower alkyl)amino}, cycloalkyl, or aralkyloxycarbonyl, are combined with their adjacent N to form a heterocyclic group (the heterocyclic group formed together with their adjacent N may contain oxygen, sulfur, or other nitrogen atoms), or are combined with their adjacent N to form a substituted heterocyclic group (the substituted heterocyclic group formed together with their adjacent N may contain oxygen, sulfur, or other nitrogen atoms, and the substituents in the substituted heterocyclic group formed together with their adjacent N have the same meanings as defined for the substituents in the substituted heterocyclic group formed together with their adjacent N described below)], N+R20R21R22Xxe2x88x92 {wherein R20 and R21 are the same or different and represent lower alkyl, or are combined with their adjacent N to form a heterocyclic group (the heterocyclic group formed together with their adjacent N may contain oxygen, sulfur, or other nitrogen atoms), R22 is lower alkyl, and X is an atom of chlorine, bromine or iodine}, OR23 {wherein R23 represents hydrogen, lower alkyl, lower alkanoyl, substituted lower alkyl {the substituted lower alkyl is replaced by at least one of hydroxy, lower alkoxy, O(CH2CH2O)nAR19A (wherein nA is an integer of 1 to 15, and R19A is lower alkyl), oxo, carboxy, lower alkoxycarbonyl, aryl, substituted aryl (the substituents in the substituted aryl have the same meanings as defined for the substituents in the substituted aryl described below), a heterocyclic group, a substituted heterocyclic group (the substituents in the substituted heterocyclic group have the same meanings as defined for the substituents in the substituted heterocyclic group described below), CONR15BR16B {wherein R15B and R16B have the same meanings as defined for R15 and R16 described above, respectively}, amino, lower alkylamino, and di(lower alkyl)amino}, aryl, substituted aryl (the substituents in the substituted aryl have the same meanings as defined for the substituents in the substituted aryl described below), a heterocyclic group, and a substituted heterocyclic group (the substituents in the substituted heterocyclic group have the same meanings as defined for the substituents in the substituted heterocyclic group described below)}, SR23A (wherein R23A has the same meaning as defined for R23 described above) or SO2R23B (wherein R23B is lower alkyl), etc. The lower alkyl moieties of the lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylamino and di(lower alkyl)amino have the same meanings as defined for the lower alkyl described above. The cycloalkyl and the lower alkenyl have the same meanings as defined for the cycloalkyl and lower alkenyl described above, respectively. The lower alkanoyl has the same meaning as defined for the lower alkanoyl described above. The aryl and the aryl moiety of the aroyl have the same meanings as defined for the aryl described above, and the aralkyl and the aralkyl moiety of the aralkyloxycarbonyl mean the aralkyl having 7 to 15 carbon atoms, for example, benzyl, phenetyl, benzhydryl, naphthylmethyl, etc. The heterocyclic group has the same meaning as defined for the heterocyclic group described above, and the heterocyclic group formed together with their adjacent N has the same meaning as defined for the heterocyclic group formed together with their adjacent N described above. The halogen has the same meaning as defined the halogen/described above.
The substituents in the substituted lower alkenyl, substituted lower alkadienyl and substituted lower alkynyl include oxo in addition to the substituents in the substituted lower alkyl described above.
The substituents in the substituted lower alkanoyl include 1 to 3 substituents which are the same or different, for example, halogen, NR17AR18A (wherein R17A and R18A have the same meanings as defined for R17 and R18 described above, respectively), etc.
The substituents in the substituted aryl and substituted aroyl include 1 to 3 substituents which are the same or different, for example, halogen, lower alkyl, substituted lower alkyl (the substituents in the substituted lower alkyl are halogen, oxo, carboxy, lower alkoxycarbonyl, amino, lower alkylamino, di(lower alkyl)amino, hydroxy or lower alkoxy), nitro, hydroxy, lower alkoxy, amino, lower alkylamino, di(lower alkyl)amino, lower alkanoyl, cyano, etc. The lower alkyl moieties in the lower alkyl, lower alkoxycarbonyl, lower alkoxy, lower alkylamino or di(lower alkyl)amino have the same meaning as defined for the lower alkyl described above. The lower alkanoyl has the same meaning as defined for the lower alkanoyl described above. The halogen has the same meaning as defined for the halogen described above.
The substituents in the substituted heterocyclic group and substituted heterocyclic group formed together with their adjacent N include oxo in addition to the substituents in the substituted aryl and the substituted aroyl described above.
The pharmaceutically acceptable salts of Compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts, etc. The acid addition salts include inorganic acid salts such as hydrochloride, sulfate and phosphate and organic acid salts such as methane sulfonate, acetate, maleate, fumarate, tartrate, citrate and lactate; the metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt, etc.; the ammonium salts include salts of ammonium, tetramethylammonium, etc.; the organic amine addition salts include addition salts of morpholine, piperidine, etc.; and the amino acid addition salts include addition salts of lysine, glycine, phenylalanine, aspartic acid, glutamic acid, etc.
The antitumor agent, which can be used in combination with the enhancers for activity provided by the present invention, includes anticancer agents having actions on DNA, for example, platina preparations such as Cisplatin and Carboplatin, Mitomycin type drugs, nitrogen mustard type drugs, nitrosourea type drugs, Camptothecine derivatives (topoisomerase I inhibitors) such as CPT-11 and Topotecan, and Etoposide (topoisomerase II inhibitor), etc., and antimetabolites, for example, 5-Fluorouracil derivatives, Cytidine derivatives such as Cytosine arabinoside (Ara-C) and Gemcitabine, Adenosine derivatives such as Fludarabine, Methotrexate derivatives, TS (thymidylic acid synthase) inhibitors such as Toumidex, etc.
Hereinafter, the processes for the production of Compound (I) are described.
Unless otherwise specified, each group in the reaction steps described below has the same meaning as defined above.
Compound (I) can be produced by the following reaction steps.
In the processes shown below, if the defined groups are changed under the conditions of the practical process or are not appropriate for the practice of the process, the objective compounds can be obtained using the methods for introducing and eliminating protective groups ordinarily used in synthetic organic chemistry [for example, T. W. Greene: Protective Groups in Organic Synthesis, John Wiley and Sons Inc. (1981)]. And also, the order of the reaction steps such as introduction of the substituents etc., can be altered, if necessary.
Process 1
Compound (Ia) that is, Compound (I) wherein R1 is hydrogen, can be produced in a known method [for example, the compound, wherein R2 or R3 is substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, a substituted or unsubstituted heterocyclic group, halogen, nitro, formyl, COR6 (wherein R6 has the same meaning as defined above), NR11R12 (wherein R11 and R12 have the same meanings as defined above, respectively), etc., can be obtained in a method described in WO88/7045, WO97/46565, etc. and the compound, wherein, R2 or R3 is formyl, lower alkanoyl, carboxy, lower alkoxycarbonyl, OR14 (wherein R14 has the same meaning as defined above), etc., can be obtained in a method described in Japanese Published Unexamined Application No.3-220194, WO94/6799, etc.] or in a method similar thereto, from Compound (II), which can be obtained in a known method [J. Am. Chem. Soc., 117, 552 (1995), J. Antibiotics, 30, 275 (1977), J. Chem. Soc., Chem. Comm., 800 (1978), etc.]
(wherein R2, R3, R4 and R5 have the same meanings as defined above, respectively).
Process 2
Compound (Ib), that is, Compound (I) wherein R1 is hydroxy or lower alkoxy, can be produced in a known method (for example, the compound, wherein R1 is hydroxy, can be obtained in a method described in WO89/7105, Japanese Published Unexamined Application No.1-168689, Japanese Published Unexamined Application No.6-9645, etc., and the compound, wherein R1 is lower alkoxy, can be obtained in a method described in WO89/7105, Japanese Published Unexamined Application No.1-168689, etc.) or in a method similar thereto, from Compound (Ia). 
(wherein R1a is hydroxy or lower alkoxy, and R2, R3, R4 and R5 have the same meanings as defined above, respectively).
Transformations of functional groups, contained in substituents in R1, R2, R3, R4 or R5 in Compound (I), obtained in the Examples, and the compounds, obtained in the Reference Examples, can also be conducted by other methods known in the art [for example, R. C. Larock: Comprehensive Organic Transformations (1989)], in addition to the method described above.
By a suitable combination of the methods described above, Compound (I) having objective functional groups at objective positions can be obtained.
The objective products in the processes described above can be isolated and purified by a suitable combination of techniques used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization and various kinds of chromatography. Further, the intermediates can also be subjected to the subsequent reaction without particular purification.
Compound (I) can exist as isomers such as regioisomers, geometrical isomers, tautomers or optical isomers, and in the present invention, all possible isomers or the mixture thereof in any ratio can be used as the antitumor agents, the enhancers for activity of an antitumor agent, and the agents for abrogating accumulation action at the G2 or S stage of the cell cycle.
Among Compound (I), compounds having the same configuration at the 9-, 10-, 11- and 13-positions as in a staurosporin shown in the following formula, are more preferred. 
In the case where a salt of Compound (I) is desired, when Compound (I) is obtained in the form of the salt, it may be directly purified, while when Compound (I) is obtained in its free form, it may be dissolved or suspended in a suitable solvent, and converted into the salt followed by adding an acid or a base thereto.
Compound (I) or pharmaceutically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts also fall under the scope of the present invention.
Specific examples of Compound (I) are shown in Table 1, and the compounds described in the Reference Examples are shown in Table 2. With respect to stereochemistry based on the substituent R1 at the 3-position, (a), (b) and (c) in the tables indicate an isomer of longer retention time, an isomer of shorter retention time, and a mixture of the two isomers, respectively, under the following conditions for high performance liquid chromatography (HPLC).
HPLC analysis was conducted as follows.
Column: YMC AM312 (50xc3x976 mm I.D.)
Mobile phase: Starting from 50% methanol-a 0.02 mol/L phosphate buffer (pH=7), the concentration of methanol was increased at a predetermined rate over 15 minutes to 100% methanol, and thereafter, the sample was eluted with 100% methanol.
Compound (I) or pharmaceutically acceptable salts thereof can be used as it is or in various pharmaceutical forms, depending on the pharmacological action thereof and the object of administration. The pharmaceutical compositions of the present invention can be produced by uniformly mixing an effective amount of Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient with a pharmaceutically acceptable carrier. The carrier can be in various forms depending on the form of a preparation desirable for administration. These pharmaceutical compositions are desirably in a unit administration form being suitable for oral administration or parenteral administration such as an ointment or injection.
For the preparation of tablets, for example, an excipient such as lactose, glucose, sucrose, mannitol or methyl cellulose, a disintegrator such as starch, sodium alginate, carboxymethyl cellulose calcium or crystalline cellulose, a lubricant such as magnesium stearate or talc, a binder such as gelatin, polyvinylalcohol, polyvinylpyrrolidone, hydroxypropyl cellulose or methyl cellulose, or a surfactant such as a sucrose fatty acid ester or a sorbitol fatty acid ester may be used in a usual manner. Tablets containing 1 to 200 mg of an active ingredient per tablet are preferred.
For the preparation of granules, for example, an excipient such as lactose or sucrose, a disintegrator such as starch, or a binder such as gelatin may be used in a usual manner.
For the preparation of powders, for example, an excipient such as lactose or mannitol may be used in a usual manner.
For the preparation of capsules, for example, gelatin, water, sucrose, gum Arabia, sorbitol, glycerin, crystalline cellulose, magnesium stearate, talc, etc., may be used in a usual manner. Capsules containing 0.1 to 200 mg of an active ingredient per capsule are preferred.
For the preparation of syrups, for example, a sugar such as sucrose, water, ethanol, etc., may be used in a usual manner.
For the preparation of ointments, for example, an ointment base such as vaseline, liquid paraffin, lanoline or Macrogol, or an emulsifier such as sodium lauryl lactate, benzalkonium chloride, a sorbitan mono-fatty acid ester, carmellose sodium, or gum Arabia, etc., may be used in a usual manner.
For the preparation of injections, for example, water, physiological saline, a vegetable oil (olive oil, peanut oil, etc.), a solvent (ethyl oleate, propylene glycol, polyethylene glycol, etc.), a solubilizing agent (sodium benzoate, sodium salicylate, urethane, etc.), an isotonizing agent (sodium chloride, glucose, etc.), a preservative (phenol, cresol, p-hydroxybenzoic acid ester, chlorobutanol, etc.), or an antioxidant (ascorbic acid, sodium pyrosulfite, etc.), may be used in a usual manner.
Compound (I) or pharmaceutically acceptable salts thereof can be administered orally or parenterally as an ointment or injection, and generally preferred to be administered in a dose of 0.1 to 200 mg/kg per day, although the effective dose and frequency of administration are varied depending on the administration form, patient""s age or weight, symptoms, etc.
Hereinafter, the activity of Compound (I) is described by reference to Test Examples.